Paper II

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Paper II

Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute

postoperative pain. The Cochrane Database of Systematic Reviews 2006, Issue 1. Art.No.:CD004603. DOI: 10.1002/14651858. CD004603.pub2.

Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute post- operative pain. A quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand 2005;49(10):1405-1428

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Perioperative ketamine for acute postoperative pain (Review)

Bell RF, Dahl JB, Moore RA, Kalso E

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library 2006, Issue 2

http://www.thecochranelibrary.com

1 Perioperative ketamine for acute postoperative pain (Review)

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T A B L E O F C O N T E N T S

1 ABSTRACT . . . .

1 PLAIN LANGUAGE SUMMARY . . . .

2 BACKGROUND . . . .

2 OBJECTIVES . . . .

2 CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . .

3 SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . .

4 METHODS OF THE REVIEW . . . .

4 DESCRIPTION OF STUDIES . . . .

6 METHODOLOGICAL QUALITY . . . .

6 RESULTS . . . .

8 DISCUSSION . . . .

9 AUTHORS’ CONCLUSIONS . . . .

9 POTENTIAL CONFLICT OF INTEREST . . . .

9 ACKNOWLEDGEMENTS . . . .

9 SOURCES OF SUPPORT . . . .

10 REFERENCES . . . .

13 TABLES . . . .

13 Characteristics of included studies . . . .

23 Characteristics of excluded studies . . . .

23 ADDITIONAL TABLES . . . .

23 Table 01. Electronic search strategies . . . .

24 ANALYSES . . . .

24 Comparison 01. Perioperative ketamine versus control . . . .

24 Comparison 02. Adverse effects . . . .

24 COVER SHEET . . . .

25 GRAPHS AND OTHER TABLES . . . .

25 Analysis 01.01. Comparison 01 Perioperative ketamine versus control, Outcome 01 Morphine (PCA) consumption over

24 hours . . . .

26 Analysis 02.01. Comparison 02 Adverse effects, Outcome 01 Nausea and vomiting . . . .

i Perioperative ketamine for acute postoperative pain (Review)

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Perioperative ketamine for acute postoperative pain (Review)

Bell RF, Dahl JB, Moore RA, Kalso E

This record should be cited as:

Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain.The Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD004603.pub2. DOI: 10.1002/14651858.CD004603.pub2.

This version first published online:25 January 2006 in Issue 1, 2006.

Date of most recent substantive amendment:17 October 2005

A B S T R A C T Background

Postoperative pain management is often limited by adverse effects such as nausea and vomiting. Adjuvant treatment with an inexpensive opioid-sparing drug such as ketamine may be of value in giving better analgesia with fewer adverse effects.

Objectives

To evaluate the effectiveness and tolerability of ketamine administered perioperatively in the treatment of acute postoperative pain in adults.

Search strategy

Studies were identified from MEDLINE (1966-2004), EMBASE (1980-2004), the Cochrane Library (2004) and by handsearching reference lists from review articles and trials. The manufacturer of ketamine (Pfizer) provided search results from their in-house database, PARDLARS.

Selection criteria

Randomised controlled trials (RCTs) of adult patients undergoing surgery, being treated with perioperative ketamine or placebo. Studies where ketamine was administered in addition to a basic analgesic (such as morphine or NSAID) in one study group, and compared with a group receiving the same basic analgesic (but without ketamine) in another group, were also included.

Data collection and analysis

Two independent reviewers identified fifty five RCTs for potential inclusion. Quality and validity assessment was performed by two independent reviewers. In the case of discrepancy, a third reviewer was consulted. Patient reported pain intensity and pain relief was assessed using visual analogue scales or verbal rating scales and adverse effects data were collated.

Main results

Thirty-seven trials were included (2240 participants). Eighteen trials were excluded.Twenty-seven of the 37 trials found that perioperative subanaesthetic doses of ketamine reduced rescue analgesic requirements or pain intensity, or both. Quantitative analysis showed that treatment with ketamine reduced 24 hour PCA morphine consumption and postoperative nausea or vomiting (PONV). Adverse effects were mild or absent.

Authors’ conclusions

Ketamine in subanaesthetic dose (that is a dose which is below that required to produce anaesthesia) is effective in reducing morphine requirements in the first 24 hours after surgery. Ketamine also reduces postoperative nausea and vomiting. Adverse effects are mild or absent.

P L A I N L A N G U A G E S U M M A R Y

Perioperative ketamine in subanaesthetic dose reduces postoperative morphine requirements and reduces postoperative nausea or vomiting (PONV).

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Adverse effects for perioperative ketamine are mild or absent. The current data cannot be translated into a specific treatment regime.

B A C K G R O U N D

Adverse effects such as nausea and vomiting often limit postoperative pain management. There are a number of reasons for postoperative nausea and vomiting (PONV), and these have been exhaus- tively discussed in the anaesthetic literature. One possible factor is the use of opioids and adjuvant treatment with opioid-sparing drugs such as ketamine may be of value in giving better analgesia with fewer adverse effects (Schmid 1999).

Ketamine is a phencyclidine derivative developed in the 1960’s as a general anaesthetic. Ketamine hydrochloride is given intravenously or intramuscularly for surgical anaesthesia. Ketamine is also used as an adjuvant to opioids in the treatment of refractory pain in cancer patients (Bell 2003), in the treatment of neuropathic pain (Fisher 2000), and in the treatment of acute postoperative pain (Schmid 1999), although not licensed for these conditions.

Ketamine for postoperative pain may be administered before incision, after incision, or in the postoperative period, and is usually given as an adjuvant to systemic opioid, for example patient-controlled analgesia (PCA). Routes of administration include intravenous, subcutaneous, epidural, transdermal and intra-articular.

Ketamine was previously only available as a racemic mixture of two enantiomers, S(+) and R(-) ketamine. The S(+) isomer has been shown to be approximately twice as potent as the racemic mixture (Arendt-Nielsen 1996). S(+) ketamine has recently been approved for clinical use in countries such as Finland and Germany. Clinical use of ketamine is limited due to psychotomimetic adverse effects such as hallucinations and bad dreams. Other common adverse effects are dizziness, blurred vision, and nausea and vomiting.

Opioids are traditionally used as a part of general anaesthesia and for the treatment of acute postoperative pain. Recent research indicates that opioids produce not only analgesia, but also hyperalgesia (Mao 2002). Consequently, perioperative (pre, per, and postoperative) opioids may increase postoperative pain and opioid requirements (Guignard 2000). Central sensitization includes an altered processing of innocuous, tactile impulses from myelinated afferents so that activation of these fibres produces painful sen- sations (Woolf 2000). The neurophysiological and biochemical mechanisms of these alterations include a decrease in inhibitory input or an increase in synaptic efficacy or membrane excitabil- ity, mediated by wind-up and neurokinin and N-methyl-D-aspartic acid receptor mechanisms (NMDA receptors) (Woolf 2000).

Wind-up is a phenomenon whereby responses of dorsal horn neu- rones increase during repetitive, constant intensity, C-fiber stim- uli, i.e. increased duration and magnitude of the cell responses.

Blockade of NMDA receptors has been shown in animal studies to prevent the development of increased pain sensitivity and opioid tolerance (Price 2000; Mao 2002). Ketamine is a non-competitive

NMDA receptor antagonist. NMDA receptor blocking could be a fruitful therapy for improving postoperative opioid effectiveness.

Ketamine could, in addition to having an opioid sparing effect, conceivably reduce the development of chronic postoperative pain through NMDA receptor blockade and reduction of wind-up and central sensitization.

Published literature indicates that ketamine is used in the perioperative setting in countries such as Greece, Brazil, India, Ger- many, UK, Israel, France, China, Denmark, Norway, and Japan for anaesthesia or as an adjuvant analgesic. However, current use of ketamine in this setting involves different practice regarding dose, route of administration and time of administration. A literature review based on an electronic search of the MEDLINE database from 1966-1998 (Schmid 1999) concludes that the role of ketamine remains controversial, but that low-dose ketamine (defined as a bolus dose of less than 2 mg/kg when given intramuscularly or less than 1 mg/kg when administered via the intravenous or epidural route) as an adjuvant to opioids or local anaesthetics may have an important role to play in the treatment of acute postoperative pain. This review will consider the evidence for the efficacy and tolerability of ketamine in the treatment of acute postoperative pain in adults.

O B J E C T I V E S

To evaluate the effectiveness and tolerability of ketamine administered perioperatively (pre, per, and postoperative) in the treatment or prevention of acute, postoperative pain in adults.

C R I T E R I A F O R C O N S I D E R I N G S T U D I E S F O R T H I S R E V I E W

Types of studies

Randomized, placebo-controlled trials described as double- blinded and where each group had a minimum of ten patients who had completed the study were included. Studies where ketamine was administered in addition to a basic analgesic (such as morphine or NSAID) in one study group, and compared with a group receiving the same basic analgesic (but without ketamine) in another group, were also included. All identified published trials were considered eligible. Only complete studies, not abstracts, were included. Duplicate publications are reported but excluded from the analysis.

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Types of participants

The population addressed by the review were patients aged 18 years or above, undergoing a surgical procedure.

Types of intervention

The intervention considered by this review was treatment with ketamine, given systemically or spinally, in any dose during the perioperative period. Participants received ketamine or placebo, or both ketamine and basic analgesic or basic analgesic alone.

The ketamine or placebo or basic analgesic was administered:

A: As a bolus dose prior to incision (pre-incisional bolus) B: As a bolus dose immediately after incision or at wound closure (post-incisional bolus)

C: An infusion (or repeated by-the-clock dosing) begun prior to incision

D: Same as C, but begun after incision

E: As a postoperative bolus or infusion, including PCA Types of outcome measures

The primary outcome measure

• For studies using PCA (E above) was total consumption of opioids or other analgesics for up to 48 hours after surgery.

• For studies not assessing or using PCA, and in the absence of rescue medication, was pain intensity assessed using subjective, validated measures of pain on movement and at rest (e.g., visual analogue scale of pain intensity (VASpi) or other validated scales). If rescue medication was given, the consumption of rescue medication was used as the outcome (Kalso 2002).

Secondary outcome measures included:

• Time from end of surgery to first request for analgesia/first trigger of PCA.

• Major and minor adverse events as judged by the author of the study, such as hallucinations, bad dreams, dizziness, blurred vision, sedation, nausea, and vomiting.

S E A R C H M E T H O D S F O R

I D E N T I F I C A T I O N O F S T U D I E S

See: Pain, Palliative and Supportive Care Group methods used in reviews.

ELECTRONIC DATABASES

To identify studies for inclusion in this review, detailed search strategies were developed for each electronic database searched.

These searches were based on the search strategy developed for the Cochrane Central Register of Controlled Trials (CENTRAL) and revised appropriately for each database. The subject search used a combination of controlled vocabulary and free text terms as follows:

#1. KETAMINE single term (MeSH)

#2. ketamine OR ketalar

#3. (#1 or #2)

#4. PAIN POSTOPERATIVE single term (MeSH)

#5. (postoperat* near pain*)

#6. (pain* next following next surg*)

#7. (pain* next following next treat*)

#8. (pain* next following next operat*)

#9. post-operat* pain

#10. ((post near surg*) or postsurg* OR post-surg*)

#11. ((post near operat*) or postoperat* OR post-operat*)

#12. pain*

#13. #10 AND #11

#14. (#13 and #12)

#15. (post-operat* near analgesi*)

#16. (postoperat* near analgesi*)

#17. (post-surg* near analgesi*)

#18. (postsurg* near analgesi*)

#19. (analgesi* near (following next surg*))

#20. (analgesi* next following next operat*)

#21. (#4 or #5 or #6 or #7 or #8 or #9 or #14 or #15 or #16 or

#17 or #18 or #19 or #20)

#22. (#3 and #21)

The search strategies for EMBASE and PARDLARS are given in Table 01.

The following electronic databases were searched:

1. Cochrane Pain, Palliative & Supportive Care Register (current issue)

2. The Cochrane Central Register of Controlled Trials (CENTRAL): The Cochrane Library (June 2004) 3. MEDLINE (1966 -June 2004)

4. EMBASE (1980 -June 2004)

5. PARDLARS (Pfizer Corporation’s in-house database) February 2003

HANDSEARCHING

Journals were not hand searched. Abstracts were checked to see if they had been published. Reference lists were handsearched (see below).

REFERENCE LISTS

The reference lists of all eligible trials, key textbooks, and relevant systematic reviews were searched for additional studies.

UNPUBLISHED DATA

The manufacturers of ketamine (Ketalar), Pfizer plc, were contacted to request access to relevant research material and unpublished data.

LANGUAGE

There was no language restriction. The search attempted to identify all relevant studies irrespective of language. Non- English papers were assessed and, if necessary, translated with the assistance of a native speaker.

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M E T H O D S O F T H E R E V I E W

STUDY SELECTION

All identified records from each of the databases were examined.

The titles and abstracts of studies were studied independently by two reviewers (RB, EK) and potentially relevant studies, including review articles, were retrieved for assessment for inclusion in the review. Each trial report which appeared to meet the criteria was independently assessed for inclusion by three reviewers (RB, JBD, EK).

DATA EXTRACTION

A data extraction form was designed and the following data items were collected:

1. Publication details

2. Patient population, number of patients, age, surgical procedure 3. Description of intervention

4. Design, study duration and follow up 5. Outcome measures

6. Analgesic outcome results 7. Withdrawals and adverse effects STUDY QUALITY AND VALIDITY

Study quality (randomization/allocation concealment; details of blinding measures (Colditz 1989; Schulz 1995); withdrawals and dropouts; overall quality score) were evaluated using the three item (1-5) Oxford Quality scale (Jadad 1996).

Validity was evaluated using the 5 item (1-16) Oxford Pain Validity Scale (OPVS) (Smith 2000). Heterogeneity tests were not used as they have previously been shown to be unhelpful (Morris 1995;

Gavaghan 2000) although clinical homogeneity was examined visually (Higgins 2002). Scoring was performed independently by two reviewers (RFB, EK). In the case of discrepancy, a third reviewer (JBD) was consulted.

ANALYSIS

Both dichotomous and continuous data were extracted. Meta- analysis was performed where appropriate. The data did not permit calculation of odds ratios, numbers needed to treat (NNTs) or numbers needed to harm (NNHs) with 95% confidence intervals.

Continuous data were analysed as weighted mean differences (WMD).

Subgroup analysis was not possible due to the heterogeneity of the trials.

D E S C R I P T I O N O F S T U D I E S

The searches identified a total of 165 possible titles. Seventy-three were excluded. Eighteen were not clinical trials. Thirty-eight were abstracts. Thirteen trials did not concern postoperative pain. One was a retrospective study. One paper (Gilabert Morell 2002) was irretrievable. Two were duplicates (Dick 1983, Knoche 1983). In addition, eight trials were not randomised and fifteen did not have

an appropriate control. Fourteen trials were not described as double-blind. A total of 55 randomised, controlled, double-blind clinical trials of perioperative administration of ketamine for postoperative pain control were identified. Eighteen trials were excluded:

five due to the adminstration form of ketamine) (two transdermal, two intra-articular, one wound instillation). Four trials were excluded because groups contained less than the minimum of ten patients who had completed the study. Nine trials were excluded due to methodological flaws. Details of these 18 trials may be seen in the table of excluded studies.

Thirty-seven trials with 53 treatment arms met the inclusion criteria (2240 participants). One study in Turkish (Talu 2002) was assessed with the help of a native speaker. Details of these trials may be seen in the table of included studies and in Additional Table 1.

These 37 trials with 53 treatment arms could be divided into:

A. 13 treatment arms with a preincisional IV or IM bolus of ketamine compared with placebo

B. 7 treatment arms with an IV-bolus of ketamine at wound closure compared with placebo

C. 13 treatment arms with a perioperative continuous infusion/

repeated boluses of IV-ketamine compared with placebo D. 7 treatment arms with administration of a preincisional bolus of epidural ketamine

E. 3 treatment arms with administration of a postincisional bolus of epidural ketamine

F. 2 treatment arms with administration of a continuous perioperative epidural infusion of ketamine compared with placebo G. 2 treatment arms with intraoperative IV ketamine versus placebo combined with postoperative PCA ketamine/morphine versus PCA morphine

H. 4 treatment arms with postoperative IV PCA ketamine/morphine, compared with IV PCA morphine

I. 2 treatment arms with patient-controlled epidural analgesia (PCEA) ketamine +morphine (and other drugs), compared with PCEA morphine (and other drugs)

Twenty-six trials had a placebo control while 11 trials with ketamine in addition to a basic regimen with morphine was compared with morphine alone. A total of 2137 patients, of which 1210 received ketamine, were studied. Pain was rated using visual analogue scale (VAS) in 34 trials, and a verbal rating scale (VRS) was used in three.

The most common route of administration of ketamine was intravenous, as a bolus or infusion, or both. In six trials ketamine was administered as an epidural bolus. PCA ketamine was used in four studies and PCEA ketamine in two. Thirty-two trials used racemic ketamine, four trials used S (+) ketamine and one trial used the R (-) isomer.

A. Studies with administration of a preincisional IV or IM bolus of ketamine compared with placebo

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Twelve trials with 13 treatment arms compared a preincisional bolus dose of ketamine with placebo. R (-) ketamine was used in one treatment arm (Mathisen 1999), S(+) ketamine in one treatment arm ( Argiriadou 2004) and racemic ketamine in 11 treatment arms.

The retrieved trials were heterogeneous. The doses of ketamine varied almost seven-fold, from 0.15 to 1.0 mg/kg IV. Different analgesics and treatment regimens were employed for rescue medication, and the surgical procedures included various gynaecological, abdominal, and orthopedic operations. Due to this disparity, a meta-analysis of the combined results was not considered rational.

In one of these trials having two treatment arms, one pre and one postincisional, all patients had been pretreated with IM ketorolac together with preincisional skin infiltration with bupivacaine (Mathisen 1999). This trial was scored as non-sensitive.

B. Studies with administration of an IV-bolus of ketamine at wound closure compared with placebo

Five trials with seven treatment arms compared a postincisional bolus dose of ketamine with placebo. R (-) ketamine was used in one (Mathisen 1999), and racemic ketamine in six treatment arms.

Again the trials were heterogenous and involved such different surgical procedures as elective outpatient surgery and abdominal hysterectomy. Ketamine doses ranged from 0.05 to 1 mg/kg. Two studies (Menigaux 2000, Mathisen 1999) used PCA opioid for postoperative pain and three studies used incremental IV-opioid bolus on request.

C. Studies with administration of a perioperative continuous infusion/repeated boluses of IV-ketamine compared with placebo Eleven trials with 13 treatment arms compared a perioperative continuous intravenous infusion/repeated IV bolus of ketamine with placebo. A ketamine infusion was used in 12 treatment arms, and repeated intraoperative bolus of ketamine at twenty minute intervals in one (Argiriadou 2004). S (+) ketamine was used in two treatment arms (Argiriadou 2004; Jaksch 2002) and racemic ketamine in 11.

The surgical procedures varied and included predominantly major abdominal and renal surgery. There was clinical heterogeneity, with wide variation in the total ketamine dose administered due to different doses and duration of infusions. In seven treatment arms, the infusion was commenced prior to incision and continued until skin closure. In one treatment arm, ketamine was commenced prior to incision and infused until a total dose of 2 mg/kg had been given (Kakinohana 2004). In five treatment arms, the infusion was commenced prior to incision and continued for 2-72 hours postoperatively. In two treatment arms, a ketamine infusion was commenced after surgery and continued in one arm for 24 hours (Adriaenssens 1999) and in the other for 48 hours (Guillou 2003).

Different analgesics and treatment regimens were employed for rescue medication, one treatment arm (Adriaenssens 1999) investigated PCA IV ketamine. Eight arms used PCA morphine for postoperative pain (table 3) while two arms used patient controlled

epidural analgesia (PCEA) morphine ( Aida 2000 A,B) and two arms used PCEA morphine and bupivacaine (Kakinohana 2004, Kararmaz 2003).

In one arm, all patients received epidural bupivacaine 2.5 mg/ml, 4 ml/hr for 0-24 hours postoperatively (Ilkjær 1998). This was a trial with negative outcome and was considered potentially non- sensitive. However, since the patients experienced pain above 30 on the VAS during movement in the early postoperative period, and to avoid bias, the trial was included in the quantitative analysis.

D. Studies with administration of a preincisional bolus of epidural ketamine

Seven trials with seven treatment arms investigated a preincisional epidural bolus of ketamine. Two trials with two treatment arms investigated a preincisional epidural bolus of ketamine and morphine compared with morphine alone. Racemic ketamine was used in six treatment arms, while S(+) ketamine was used in one (Himmelseher 2001). These trials concerned major surgical procedures such as total abdominal hysterectomy, colectomy, gastrectomy and total knee arthroplasty. The ketamine doses varied from 0.25 mg/kg bolus to 1 mg/kg.

E.Studies with administration of a postincisional bolus of epidural ketamine

Three trials with three treatment arms investigated a postincisional epidural bolus of ketamine. Two trials investigated epidural ketamine + morphine, compared with epidural morphine alone (Santawat 2002, Subramaniam 2001(b)). One trial compared epidural ketamine with placebo (Abdel-Ghaffar 1998). All trials used racemic ketamine. Two trials used a ketamine dose of 30 mg while the third trial used a dose of 1 mg/kg.

F.Studies with administration of a continuous perioperative epidural infusion of ketamine compared with placebo

One trial with two treatment arms (De Kock 2001) investigated an epidural bolus of ketamine followed by an epidural infusion of ketamine until the end of surgery, compared to a control group (no ketamine). This trial used racemic ketamine at a dose of 0.25 mg/kg bolus + 0.125 mg/kg/h in one treatment arm and 0.5 mg/kg and 0.25 mg/kg/h in the other.

G. Studies with intraoperative IV ketamine versus placebo combined with postoperative PCA ketamine/morphine versus PCA morphine

Two trials with two treatment arms investigated intraoperative IV ketamine combined with postoperative PCA ketamine + morphine, compared to peroperative placebo and postoperative PCA morphine. One trial (Snijdelaar 2004) used a preincisional IV bolus of S (+) ketamine 0.1 mg/ kg followed by a continuous infusion of 0.002 mg/kg/min until skin closure and IV PCA ketamine + morphine, with bolus dose of 0.5 mg ketamine + 1 mg morphine.

The second trial (Hercock 1999) used a single 0.3 mg/kg IV bolus of racemic ketamine after induction and postoperative IV PCA ketamine 1 mg/ml + morphine 1 mg/ml.

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H.Studies with postoperative IV PCA ketamine/morphine, compared with IV PCA morphine

Four trials with four treatment arms investigated postoperative IV PCA ketamine + morphine, compared to IV PCA morphine.

Racemic ketamine was used in all trials. Doses ranged from 0.75 to 2 mg/ml. The morphine dose was 1 mg/ml in three trials and 0.4 mg/ml in one trial. One trial was judged to be potentially non- sensitive since 60-70% of the patients were pain free for the first four hours after surgery (Murdoch 2002).

I.Studies with PCEA ketamine +morphine (and other drugs), compared with PCEA morphine (and other drugs)

Two trials with two treatment arms investigated PCEA ketamine + morphine , compared with PCEA morphine. These studies were performed in patients undergoing major thoracic or abdominal surgery. Racemic ketamine was used in both treatment arms. One treatment arm used a multimodal PCEA regime, with a basal infusion of ketamine 0.4 mg/ml + morphine 0.02 mg/ml, in addition to bupivacaine and epinephrine, and a bolus dose of 2.5 ml (Chia 1998). The other treatment arm used a loading dose of ketamine 5 mg + morphine 1 mg, followed by a basal infusion with ketamine 0.5 mg/ml + morphine 0.2 mg/ml, 1 ml/h and 1 ml bolus (Tan 1999).

M E T H O D O L O G I C A L Q U A L I T Y

The included studies were assessed by three independent reviewers using two quality measures: the Oxford scale (Jadad 1996) and the Oxford Pain Validity Scale (Smith 2000).

Quality and validity scores were generally high with a mean quality score of 3.9 and a mean validity score of 10.3. Three trials were considered non-sensitive (Ilkjær 1998, Mathisen 1999, Murdoch 2002).

R E S U L T S

A. Studies with administration of a preincisional IV or IM bolus of ketamine compared with placebo (13 treatment arms, N (ketamine treated) =266)

Postoperative analgesic requirements were reduced by preincisional ketamine bolus in eight out of 13 treatment arms. In one treatment arm postoperative morphine consumption was reduced by over 50% (Kwok 2004). In two treatment arms, postoperative morphine consumption was reduced by over 40% (Menigaux 2000; Roytblat 1993). In one treatment arm, the number of patients requiring morphine was reduced from 9/25 to 3/25 (Meni- gaux 2001). In two treatment arms the number of rescue doses of IM diclofenac was reduced from 4 to 2, and from 3 to 1.5, respectively (Lauretti 1996). In five treatment arms there was no significant difference in postoperative analgesic requirements between ketamine and placebo groups.

VAS pain scores were reduced for up to 24 hours postoperatively in seven of the 13 treatment arms.

B. Studies with administration of an IV-bolus of ketamine at wound closure compared with placebo (seven treatment arms, N (ketamine treated) =212)

In three of seven treatment arms, postoperative morphine requirements were reduced by postincisional ketamine. In one trial, morphine consumption was reduced by 50% (Menigaux 2000). In another trial with three treatment arms, ketamine doses of 75µg/kg and 100 µg/kg IV, given together with morphine 50 µg/kg IV reduced postoperative morphine requirements by approximately 40% (Suzuki 1999). A ketamine dose of 50µg/kg IV had less effect on both morphine consumption and pain scores.

VAS pain scores were reduced in four out of seven treatment arms:

for up to 45 minutes postoperatively in three treatment arms and up to six hours postoperatively in one treatment arm. In three treatment arms there was no significant difference in VAS pain scores.

C. Studies with administration of a perioperative continuous infusion/ repeated boluses of IV-ketamine compared with placebo (13 treatment arms, N (ketamine treated) =290)

Ketamine treatment reduced postoperative analgesic requirements in 9 out of 13 treatment arms. In one treatment arm, morphine consumption was reduced by approximately 30% (Guig- nard 2002). In another trial with two ketamine treatment arms, the combination of peroperative epidural morphine and IV ketamine gave 100% reduction in postoperative morphine requirements, while IV ketamine gave approximately 14% reduction (Aida 2000). In one treatment arm, PCA morphine consumption was reduced approximately 30 % from 0-24 hours, while cumulative morphine requirements at 48 hours in the placebo group were almost twice that of the ketamine group (Adriaenssens 1999).

VAS pain scores were reduced in seven out of 13 treatment arms:

at one hour in two arms, up to six hrs in two arms, and up to 48 hours postoperatively in another two treatment arms (Aida 2000).

In one treatment arm, both VAS at rest and on movement were reduced at all time points (Kakinohana 2004). In one treatment arm VAS at rest was reduced from 0-6 hrs, while VAS on coughing was reduced at all timepoints (Kararmaz 2003). There was no difference detected in pain scores in 6 of 13 treatment arms.

D. Studies with administration of a preincisional bolus of epidural ketamine (seven treatment arms, N (ketamine treated) = 119) Consumption of rescue analgesics was reduced in only two out of seven treatment arms. In one treatment arm, the consumption of PCEA bupivacaine and fentanyl was reduced approximately 50%

4-24 hours postoperatively (Abdel-Ghaffar 1998).

Pain scores were reduced in three out of seven treatment arms.

One trial did not provide pain score data (Subramaniam 2001(a)).

E.Studies with administration of a postincisional bolus of epidural ketamine (three treatment arms, N (ketamine treated)=61)

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Analgesic consumption was reduced in two out of three treatment arms. Two treatment arms found no difference in pain scores. The third trial (Subramaniam 2001(b)) did not provide pain score data.

F.Studies with administration of a continuous perioperative epidural infusion of ketamine compared with placebo (two treatment arms, N (ketamine treated)=40)

There was no significant difference in postoperative analgesic consumption or pain scores.

G. Studies with intraoperative IV ketamine versus placebo combined with postoperative PCA ketamine/morphine versus PCA morphine (two treatment arms, N(ketamine treated)=37 Cumulative morphine consumption and pain scores at rest were reduced in one treatment arm (Snijdelaar 2004). There was no difference in morphine consumption or pain scores in the other treatment arm.

H.Studies with postop IV PCA ketamine/morphine, compared with IV PCA morphine (four treatment arms, N (ketamine treated)=110

Morphine consumption was reduced in two out of four treatment arms. In one trial (Javery 1996), mean morphine consumption was reduced by 50%, from 51.1 mg to 25.82 mg.

Pain scores were reduced in three out of four treatment arms.

I.Studies with PCEA ketamine +morphine (and other drugs), compared with PCEA morphine (and other drugs) (2 treatment arms, N (ketamine treated) =75)

Analgesic consumption was reduced in both treatment arms. In one treatment arm, the mean 24 hour cumulative analgesic volume was reduced from 96.6 ml to 74 ml. In the other treatment arm, the 24 hour mean morphine consumption was reduced from 8.6 mg to 6.2 mg.

Pain scores were reduced in both treatment arms. VAS at rest and on coughing was reduced on Day one in one, and VAS at rest was reduced from 0-3 hours in the other.

In summary, the need for rescue medication was reduced in 29 out of 53 treatment arms, whereas VAS or VRS pain intensity scores were reduced in 27 out of 51 treatment arms, pain score data not being given in the two remaining arms. No study reported an increased need for rescue medication, or higher VAS scores in the ketamine group.

When individual trials, rather than treatment arms, were examined, 27 out of 37 trials found that perioperative ketamine reduced rescue analgesic requirements or pain intensity, or both.

Ketamine dose

All trials used ketamine in subanaesthetic dose. The question of optimal ketamine dose is not resolved by these heterogenous trials. Out of interest, we wanted to see whether there was a dose- dependent effect. Using an “average” weight of 70 kg, we roughly calculated the mean 24 hour dose of ketamine for each of the trials included in the 24 hr PCA morphine meta-analysis. The trials

could be divided into 4 groups: one group with an estimated dose of approximately 10 mg, one group with estimated dose of about 30 mg, a third group with estimated dose of about 65 mg and a fourth group with estimated dose 250-270 mg. Interestingly there seemed to be no increased morphine-sparing effect on increasing the ketamine dose above an estimated dose of 30 mg/ 24 hours.

Adverse effects

Two trials (Aida 2000, Talu 2002) did not report on adverse effects.

In general, the occurrence of adverse effects was similar in ketamine and placebo treated groups.

Psychotomimetic adverse effects

Twenty-one of 37 trials specifically stated that there were no psychotomimetic adverse effects such as hallucinations, bad dreams or dysphoria. Psychotomimetic adverse effects were reported in four trials (Burstal 2001, Ilkjær 1998, Javery 1996, Subramaniam 2001(b)). Ilkjær 1998 reported that two patients in the ketamine group, and one in the placebo group, experienced psychomimetic side effects. Burstal 2001 reported withdrawal of four patients in the ketamine group due to dysphoria. Subramaniam 2001(b) reported one patient developing hallucinations after preoperative administration of ketamine, but no psychotomimetic adverse effects in the postoperative period. Javery 1996 reported one patient in the ketamine group experiencing dysphoria, compared with three in the control group.

Nausea and vomiting

One trial reported significantly less nausea in the ketamine treated group compared to placebo (Adriaenssens 1999). One trial reported significantly less nausea in the ketamine + morphine treated group, compared with the morphine group (Javery 1996).

One trial reported significantly less nausea, vomiting and use of antiemetics in the ketamine group on the first postoperative day (Stubhaug 1997).

Sedation

Four trials (Guignard 2002; Ilkjær 1998; Mathisen 1999; Sub- ramaniam 2001(a)) reported increased sedation in the ketamine- treated groups: Ilkjær 1998 reported significantly higher sedation scores for 0-24 hours after surgery. Guignard 2002 reported higher sedation scores for the first 15 minutes after extubation.

Mathisen 1999 found that the placebo-treated group opened their eyes significantly faster and were extubated earlier than the R(- ) ketamine treated groups. Subramaniam 2001(a) reported high sedation scores in six patients in the ketamine group, compared to none in the control group, for the first two hours after surgery, but no difference thereafter.

Diplopia

Diplopia as an adverse effect of ketamine was reported in three trials (Adriaenssens 1999, Jaksch 2002, Kararmaz 2003). Adri- aenssens 1999 reported that two out of 15 ketamine treated patients experienced diplopia, while Jaksch 2002 reported diplopia in one out of 15 patients in the ketamine group. Kararmaz 2003

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reported diplopia in three ketamine-treated patients, compared with none in the control group.

Quantitative Data Synthesis

The data did not permit the calculation of odds ratios, numbers- needed-to-treat (NNTs) or numbers-needed-to-harm (NNHs).

Meta-analysis of studies employing postoperative PCA-morphine Twelve trials (Adriaenssens 1999; De Kock 2001; Guignard 2002;

Guillou 2003; Ilkjær 1998; Jaksch 2002; Javery 1996; Menigaux 2000; Murdoch 2002; Roytblat 1993; Snijdelaar 2004; Stubhaug 1997) provided data on 24 hour cumulative IV PCA morphine consumption. The authors of nine trials were contacted in order to get the data expressed as means +/- SD. Six authors kindly provided the necessary data. Though the author of one trial (Roytblat 1993) could not be contacted, the data could be extracted from a figure.

In two trials (De Kock 2001, Murdoch 2002) it was not possible to obtain the requested data.

In a total of 10 trials with 11 treatment arms and a total of 432 patients, treatment with ketamine significantly reduced PCA morphine consumption in the first 24 hours after surgery (WMD -15.98 mg with 95% CI (-19.70,-12.26 )).

Meta-analysis of adverse effects with ketamine

Twenty-six out of 37 trials provided dichotomous data on nausea and vomiting, or nausea or vomiting. The total number of patients in the comparison was 1261. When all data was combined, treatment with ketamine significantly reduced postoperative nausea and vomiting (p=0.001). When the data for nausea and for vomiting alone were analysed, treatment with ketamine reduced nausea (p=0.03) and vomiting (p=0.002). When the data from trials included in the 24 hour PCA morphine consumption analysis was examined separately, ketamine reduced nausea and vomiting (p=0.03).

D I S C U S S I O N

The objective of this systematic review was to assess the effectiveness and adverse effects of perioperative ketamine in the treatment of acute postoperative pain. Twenty-seven of 37 trials found that perioperative ketamine reduced rescue analgesic requirements or pain intensity, or both. Ten trials found no significant difference between ketamine and placebo, three of which were considered non-sensitive.

During the preparation of this review, two systematic reviews in- vestigating ketamine for postoperative pain were published (Sub- ramaniam 2004, Elia 2005). The authors of the first review (Subra- maniam 2004) included 37 trials, including studies performed in children and also some trials excluded by our review. The primary outcome considered by the Subramaniam review was VAS scores in the first 24 hours after surgery. Due to the heterogeneity of the data, we have chosen to restrict quantitative analysis to 24 hour

PCA morphine consumption and data on PONV. PCA morphine requirement is not the same as postoperative analgesic efficacy and not directly translatable to effect on postoperative pain, however use of rescue medication and pain intensity scores are common outcome measures in studies of postoperative pain.

The second review (Elia 2005) has similar findings to our own, with ketamine giving a clear decrease in 24 hour cumulative morphine consumption with a weighted mean difference of -15.7 mg.

In contrast to our review, the authors found no decrease in PONV.

This review included studies performed in children and in adults.

Ten trials with 11 treatment arms and 417 patients in the comparison, provided extractable data on 24 hour PCA morphine consumption. When this data was combined, ketamine was shown to be effective in reducing postoperative morphine requirements.

This should be interpreted with caution since the number of patients is small, and doses and time of administration differ widely between trials. Performing separate meta-analysis on data from the separate treatment arms was considered but decided against, since the data were heterogenous and the number of patients in each analysis would be very small. The meta-analysis gave a weighted mean difference (WMD) of 15.98 mg. The clinical relevance of this dose reduction in the first 24 hours after surgery may be de- bated. When individual trial data were examined, including trials that were not included in the quantitative analysis, ketamine was generally reported to give a 30-50% reduction of rescue analgesics.

A reduction of this order may well be clinically significant, especially in selected patient groups. Perioperative ketamine may be useful for patients who traditionally require larger doses of opioids, such as cancer patients on long-term opioid therapy or the drug- dependent patient population. Patients who are especially sensitive to the adverse effects of opioids, such as the elderly, may also be a target group for this treatment. Randomised, placebo controlled trials in these patient groups would be clinically relevant.

Eliaet al. found that ketamine treatment did not reduce morphine- related adverse effects. They also found that the highest risk of hallucinations was in awake or sedated patients receiving ketamine without benzodiazepine, and that in patients undergoing general anaesthesia, the risk of hallucinations was low and independent of benzodiazepine premedication. In this review where surgery was performed under general anaesthesia in 35 of the 37 included trials, ketamine-related adverse effects were mild or absent. Eliaet al.

analysing data from 391 patients treated with ketamine and 284 patients receiving control, found no decrease in PONV. In contrast, our analysis of data from 705 patients treated with ketamine and 578 patients receiving control, showed a significant reduction of nausea and vomiting in ketamine-treated patients.

Issues of optimal dose and form of administration are not resolved by these trials. The most common route of administration for ketamine was intravenous bolus or infusion, or both, while 10 studies investigated epidural ketamine. Spinal ketamine is not a recommended route of administration due to unclear toxicity issues

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(Schmid 1999). Whether the isomers S(+) or R(-) ketamine have advantages over the racemate is not clear from the current data.

Three studies (Ilkjær 1998; Mathisen 1999; Murdoch 2002) were considered to be non-sensitive. The issue of study sensitivity in trial design is important. In general, sensitivity measures cannot be used for studies with PCA analgesic consumption as an endpoint (Kalso 2002). However, there are a number of factors which may decrease study sensitivity and which should be considered when designing clinical trials on postoperative pain. In one trial, all patients received a constant infusion of bupivacaine postoperatively (Ilkjær 1998) while in another, all patients received pretreatment with ketorolac and preincisional skin infiltration with bupivacaine (Mathisen 1999). These factors may have been responsible for low levels of pain. These studies could produce false negative results as they would be unable to detect a difference between ketamine and placebo had there been one.

Only one study (De Kock 2001) included long-term follow-up regarding mechanical hyperalgesia and residual pain. An important question which has not been addressed in the current literature is whether ketamine prevents the development of hyperalgesia during surgery and/ or the development of chronic postsurgical pain. NMDA receptor antagonists, including ketamine, have been shown to prevent the development of hyperalgesia (Eide 1994, Angst 2003). Chronic postsurgical pain is more common than previously thought (Kalso 1992; Perttunen 1999; Nikolajsen 2004;

Perkins 2000). Certain types of surgical intervention, for example thoracotomy and mastectomy, have a relatively high prevalence of chronic postsurgical pain. Studies with long term follow-up in these patient groups would therefore be of interest.

Ketamine is a readily available, inexpensive drug. It is generally thought that it has limited usefulness in pain management due to adverse effects. This is not supported by the current evidence in relation to acute postoperative pain in adults where adverse effects were mild or absent. In fact, ketamine reduces postoperative nausea and vomiting. Because both ketamine and morphine are reported to cause nausea and vomiting, it is interesting that a combination of morphine and ketamine appears to reduce PONV.

When low-dose ketamine is given to healthy volunteers, the in- cidence of nausea and vomiting appears to be greater than that reported in the clinical setting (Schmid 1999). The observed reduction in PONV in the studies included in this review may be due to a morphine-sparing effect or to other as yet undetermined factors. Not all trials provided extractable data regarding nausea and vomiting. It is recommended that future trials report adverse effects as dichotomous data.

The large number of papers retrieved shows that there is consid- erable interest in the use of ketamine for acute postoperative pain.

A number of studies are only published as abstracts. It will be in-

teresting to see whether they are ultimately published, and how the new data will contribute to current findings.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Ketamine in subanaesthetic dose is effective in reducing morphine requirements in the first 24 hours after surgery. Adverse effects are mild or absent. Ketamine reduces postoperative nausea and vomiting.

The retrieved studies were heterogenous and the result of the meta- analysis can not be translated into any specific administration- regimen with ketamine.

Implications for research

Future trials should focus on optimal dose, dosing time and dosing periods, and have long-term follow-up with regard to the development of hyperalgesia and chronic postsurgical pain. Trials of perioperative ketamine in selected patient groups where opioid- sparing is desirable would be of interest. Better reporting of adverse effects, for example as dichotomous data, is required.

P O T E N T I A L C O N F L I C T O F I N T E R E S T

RFB, JBD, RAM and EK have consulted for various pharmaceutical companies. RFB, JBD, RAM and EK have received lecture fees from pharmaceutical companies related to analgesics. No author has any direct stock holding in any pharmaceutical company.

A C K N O W L E D G E M E N T S

Searches were performed by Frances Fairman at the Cochrane Pain, Palliative and Supportive Care Collaborative review group (PaPas), Oxford UK. Phil Wiffen at PaPas gave valuable input.

The review was supported by grants from the Research Council of Norway and the Regional Centre of Excellence in Palliative Care, Western Norway.

S O U R C E S O F S U P P O R T

External sources of support

• The Research Council of Norway NORWAY Internal sources of support

• Regional Centre of Excellence in Palliative Care, Western Nor- way, Haukeland University Hospital NORWAY

• Oxford Pain Research Funds UK

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R E F E R E N C E S

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Menigaux 2000{published data only}

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